Swiercz Jakub M, Kuner Rohini, Offermanns Stefan
Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
J Cell Biol. 2004 Jun 21;165(6):869-80. doi: 10.1083/jcb.200312094.
Plexins are widely expressed transmembrane proteins that mediate the effects of semaphorins. The molecular mechanisms of plexin-mediated signal transduction are still rather unclear. Plexin-B1 has recently been shown to mediate activation of RhoA through a stable interaction with the Rho guanine nucleotide exchange factors PDZ-RhoGEF and LARG. However, it is unclear how the activity of plexin-B1 and its downstream effectors is regulated by its ligand Sema4D. Here, we show that plexin-B family members stably associate with the receptor tyrosine kinase ErbB-2. Binding of Sema4D to plexin-B1 stimulates the intrinsic tyrosine kinase activity of ErbB-2, resulting in the phosphorylation of both plexin-B1 and ErbB-2. A dominant-negative form of ErbB-2 blocks Sema4D-induced RhoA activation as well as axonal growth cone collapse in primary hippocampal neurons. Our data indicate that ErbB-2 is an important component of the plexin-B receptor system and that ErbB-2-mediated phosphorylation of plexin-B1 is critically involved in Sema4D-induced RhoA activation, which underlies cellular phenomena downstream of plexin-B1, including axonal growth cone collapse.
丛状蛋白是广泛表达的跨膜蛋白，介导信号素的作用。丛状蛋白介导的信号转导分子机制仍相当不清楚。最近发现丛状蛋白-B1通过与Rho鸟嘌呤核苷酸交换因子PDZ-RhoGEF和LARG稳定相互作用来介导RhoA的激活。然而，尚不清楚丛状蛋白-B1及其下游效应器的活性如何受其配体Sema4D调控。在此，我们表明丛状蛋白-B家族成员与受体酪氨酸激酶ErbB-2稳定结合。Sema4D与丛状蛋白-B1结合可刺激ErbB-2的内在酪氨酸激酶活性，导致丛状蛋白-B1和ErbB-2均发生磷酸化。ErbB-2的显性负性形式可阻断Sema4D诱导的RhoA激活以及原代海马神经元中的轴突生长锥塌陷。我们的数据表明，ErbB-2是丛状蛋白-B受体系统中的重要组成部分，且ErbB-2介导的丛状蛋白-B1磷酸化在Sema4D诱导的RhoA激活中起关键作用，而RhoA激活是丛状蛋白-B1下游细胞现象（包括轴突生长锥塌陷）的基础。
